CN103462948A - Preparation method for novel non-alcoholic fatty liver disease model - Google Patents
Preparation method for novel non-alcoholic fatty liver disease model Download PDFInfo
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Abstract
The invention discloses a preparation method for a novel non-alcoholic fatty liver disease model. The preparation method comprises the following steps: a, randomly dividing fed mice into two groups, with one group being a model group and the other group being control mice, recording states everyday and taking urine, hepatic tissue and blood for lipid analysis; b, processing experimental subjects; c, building a model; d, collecting hepatic tissue and blood; e, preparing conventional frozen sections from hepatic tissue specimens of the mice, taking materials, wrapping the frozen sections with common glue and then successively carrying out dyeing and sealing; f, carrying out conventional pathological examination on model mice; g, carrying out conventional pathological examination on control mice; and h, comparing results of dynamic analysis of hepatic tissue fat obtained in step f and step g. The novel non-alcoholic fatty liver disease model established in the invention has the advantages of reasonable route, easy operation and strong pertinency and is an effective tool for further research on the non-alcoholic fatty liver disease.
Description
Technical field
This invention relates to a kind of mankind's non-alcoholic fatty liver disease (NAFLD) model preparation method.Specifically can be used for the parsing of mankind NAFLD mechanism, diagnostic method evaluation, drug screening and control, belong to medical domain.
Background technology
Non-alcoholic fatty liver disease (NAFLD) minute constitutional and the large class of Secondary cases two, the former is relevant with insulin resistant and genetic predisposition, and the latter is by due to some cause specific.Too fast and the overweight of body weight gain due to overnutrition, the metabolism syndromes such as obesity, diabetes, the hyperlipemia fatty liver of being correlated with, and hidden source property fatty liver all belongs to constitutional non-alcohol fatty liver category; After malnutrition, total parenteral nutrition, bariatric surgery sharply decline of body weight, medicine, environment and industrial poison poisoning etc. due to fatty liver belong to Secondary cases non-alcohol fatty liver category.
Difference according to pathogenesis of fatty liver mechanism, the models such as non-alcoholic and other fatty liver diseases have been set up, being divided into the sudden change of spontaneous or induction of genetic causes and the large class of acquired Models of Fatty Liver two day after tomorrow, the latter processes modeling by food or pharmacology usually, modeling method is divided into the CMDD feedstuff animal model of improvement, the high fat diet animal model, high-carbonhydrate diet Models of Fatty Liver and other as aromatase gene C yp9 knocks out, poisonous substance (carbon tetrachloride) and medicine (high fat+tetracycline injection) model etc.Advantage is for the mankind NAFLD a certain Discussion of factors mechanism of falling ill; Not enough is high sugar, high fat or gene knockout, occurs with mankind NAFLD, developmental difference is larger, and is difficult to regulation and control.Also there is no at present document to show to build that non-genomic knocks out, the NAFLD metabolic regulation model of non-higher fatty acid, non-high sugar, and the foundation of this model is to inquiring into the lipid metabolism abnormal mechanism, the control that promotes NAFLD is more useful.
Summary of the invention
It is a kind of under the normal diet state that main task of the present invention is to provide, and utilizes carnitine in exogenous carnitine analog antagonist, makes fat metabolism generation obstacle in hepatic mitochondria, sets up a kind of preparation method of novel non-alcoholic fatty liver disease model.
In order to solve above technical problem, the solution of the present invention is as follows:
A kind of novel non-alcoholic fatty liver disease model preparation method comprises the following steps:
Model preparation: adopt wild type in male 4～6 week age (
wt/wt) field rodent, in clean environment, raise; Divide two groups at random, first group: model group: second group: control mice;
A, with normal feed control mice, in body carnitine concentration be fat oxidation must (the synthetic amount of normal diet and body have met metabolism and has required);
B, model mice is adopted and transport the carrier (carnitine) that long-chain fatty acid enters the oxidation of line grain in the abdominal cavity antagonist, cause hepatic tissue fat and continue accumulation, progressively form NAFLD, set up that non-genomic knocks out, non-high sugar/higher fatty acid and the NAFLD similar model of falling ill;
The collection of c, hepatic tissue and blood: respectively two groups of mices are placed in sealed container, add diethyl ether solution, when the mice inertia, its extremity and head are fixed on flat board, the alcohol disinfecting abdominal part, cut open the belly rapidly, from the blood sampling of the Mus heart, take out hepatic tissue, be cut into size and be the piece of tissue of 5 cm * 0. 3 cm of 1. 5 cm * 1., be placed on respectively AAF mixed stationary liquid (ethanol, acetic acid, neutral formalin, V/V/V, referring to permitted equality (Henan Medical Univ.'s journal, 1999,34 (4): the method for 75) introducing is fixed;
D, adopt Leica-CM1900 type cryostat and Feather disposable blade to carry out conventional frozen section to the hepatic tissue specimen rat liver, draw materials, mounting after common glue embedding (freezing), section, dyeing.
E, the model mice routine is carried out to pathologic finding (H& E dyeing); Rat liver carries out fat stains with oil red O method, dynamic analysis hepatic tissue athero;
F, the control mice routine is carried out to pathologic finding (H& E dyeing), rat liver carries out fat stains with oil red O method, dynamic analysis hepatic tissue fat;
G, by f) and dynamic analysis hepatic tissue fat g) drawn in step contrasted, draw hepatic tissue Fat Accumulation in fatty acid and total fatty acids dynamic change model process of establishing, in hepatic tissue long-chain fatty acid, short-chain fatty acid and total fatty acids, peripheral blood, long-chain fatty acid, short-chain fatty acid and total fatty acids level change.
On above basis, described c) in step, the carnitine antagonist is [3-(2,2,2-trimethyl hydrazinium) propionate dihydrate, THP], abdominal cavity through the using method of antagonism technology is: according to the ABW of mice, press 0.05%(W/W every day) calculate the THP consumption, with 0.85%NaCl, dissolve, through one times/day of lumbar injection, inject 2～4 weeks, long-chain fatty acid can not enter mitochondrial oxidation, the hepatic tissue Fat Accumulation because lacking carrier.
On the basis of the above, described two groups of wild types (
wt/wt) mice all is placed in humidity 55%, temperature is 22 ± 2 ℃, the isoperibol that 12 hours daytime/Polygonm multiflorum Thunb replace is raised, and records body weight, active state every day, leaves and takes urine, leaves and takes hepatic tissue and make pathology inspection and lipid analysis, leaves and takes blood and makes lipid analysis.
On the basis of the above, described control mice is with equivalent 0.85%NaCl(W/V) solution, with THP injection same procedure, through lumbar injection and raising.
On the basis of the above, described f) in step, rat liver carries out fat stains with oil red O method, fatty acid accumulation in dynamic analysis hepatic tissue and blood.Concrete steps are as follows:
1, murine liver tissue is fixing with 10% formalin solution (V/V), frozen section, thick 10 μ m;
2, (take 0.5g oil red O, with 1,2-PD (Sigma, Cat#P4347), 100 ml dissolve preparation oil red O stain liquid, put in port grinding bottle and save backup;
3, entering 50% ethanol (V/V) after chip drying slightly washes;
4, the effect of oil red O dye liquor is 8 minutes;
5,50% ethanol (V/V) differentiation, tap water stops differentiation;
6, conventional haematoxylin is redyed core, and distilled water returns indigo plant, the glycerin gelatine mounting;
7, the fat drop in hepatocyte takes on a red color, and it is blue that nucleus is.
8, hepatic tissue and blood fatty acid analysis method, referring to (Clin Chim Acta, 1972 such as Ccederblad; The method of 37:235-243) introducing.
Advantage of the present invention:
1, as shown in Figure 1, biological body fat, activated generation acyl-CoA, need carnitine delivery in blood to enter liver cell mitochondria, and carnitine repeats transhipment work again through mitochondrion.Adventitia CPT-I changes acyl and carnitine into acyl carnitine, and inner membrance CPT-II carries out beta oxidation after being translated into acyl CoA, and in body, long-chain fatty acid needs the carnitine transhipment to enter the substrate oxidation by mitochondrion, generates the ATP energy supply.In whole mechanism metabolic process, carnitine, as a means of transport in human body, plays a part to form a connecting link, and from this mechanism, also can find out, the quantity of carnitine or workload to a certain extent, affect the sickness rate of fatty liver.
Specific as follows:
Under the state of body diseases or because of some factor as viral infection after, multiple endogenous metabolism thing and carnitine competition combination, occur that carnitine shortage, acyl-CoA and fatty acid gather; Or high thermic CPT-II is active low, the carnitine transit barrier; Or the picked-up hyperliposis surpasses the formation NAFLD such as carnitine disposal ability.
According to above-mentioned principle, for this metabolic process, design adopts the carnitine analog, and [3-(2,2,2-trimethyl hydrazinium) propionate dihydrate, THP, Fig. 2] the interior carnitine of antagonist, make lipodystrophy, set up the NAFLD model, as shown in Figure 3.
The novel non-alcoholic fatty liver disease model that the present invention sets up, route is reasonable, easy to operate, and with strong points, is the effective tool of further studying non-alcoholic fatty liver disease.
2, application prospect of the present invention:
NAFLD is except ethanol and other clear and definite damage liver factors, due to take diffusivity hepatocyte Macrovesicular steatosis as main, the too much clinical pathology syndrome of liver accumulation of lipid, the fat hepatitis and the liver cirrhosis that comprise simple fatty liver and differentiation, surpass the heavy degree of liver by liver fat and be divided into slightly (5%), moderate (10%) and severe (25%) fatty liver.NAFLD patient's free fatty acid (FFA) increase, liver synthesizes triacylglycerol (TG) to be increased, and the synthetic lipoprotein lipase function of hepatocyte and removing TG ability all lower simultaneously; Blood FFA increases oppositely inhibition insulin signaling transmission, promotes that NAFLD occurs, development.
In recent years, along with economic development people's living standard and lifestyle change, the NAFLD sickness rate obviously rises (15～31%), has been the primary cause of disease of state's chronic hepatopathys such as Europe, the United States, day and abnormal liver function, has become China's preclinical medicine and clinical medical new challenge.The NAFLD mechanism is illustrated not yet fully, and at present desirable NAFLD body, study model is to be badly in need of the major issue solved.Transport the carnitine that long-chain fatty acid enters mitochondrial oxidation in antagonist, liver lipid metabolism is obstructed and forms the liver fat generation, create non-high sugar or non-high fat diet, non-genomic knocks out and approach the new model of easy-regulating and evaluation with mankind NAFLD.New model contributes to the parsing of mankind NAFLD mechanism, diagnostic method evaluation, drug screening and control.
The accompanying drawing explanation
Fig. 1 carnitine delivery fat enters liver cell mitochondria oxidation schematic diagram
Fig. 2 carnitine antagonist THP molecular structure
Fig. 3 mice NAFLD illustraton of model
The comparative analysis of the tissue fat dyeing after significant quantities of fat is gathered appears in Fig. 4 hepatic tissue.
Left figure: low power is observed; Right figure: high power is observed
Upper figure: contrast Mus: figure below: model mouse
The dynamic model of Fig. 5 murine liver tissue Fat Accumulation is made comparison diagram
A: the model mouse liver fat is gathered figure, B: the dirty figure of matched group Hepar Mus
Hepatic tissue weightening finish and other comparison diagram after Fig. 6 mice THP antagonism.
The specific embodiment
Employing C57BJ/6j wild type (
wt/wt) mice cooked model mouse and two groups of Mus of contrast, equal 4 weeks age, normally raising in clean environment; Feeding environment: constant temperature (22 ± 2 ℃), temperature is that 55%, 12 hour daytime/Polygonm multiflorum Thunb replaces; Record body weight, active state every day, leave and take urine, leave and take hepatic tissue and make pathology inspection and lipid analysis, leave and take blood and make lipid analysis.
Model mouse is through THP lumbar injection antagonism carnitine (by the mice ABW, calculating 0.05%(W/W) THP consumption, with 0.85%NaCl(W/V) dissolve, through one times/day of lumbar injection, inject 2 weeks.
The contrast Mus with equivalent 0.85%NaCl(W/V) solution, with THP injection same procedure, through lumbar injection and raising.
Above-mentioned two groups of mices are carried out to the collection of hepatic tissue and blood: respectively two groups of mices are placed in sealed container, add diethyl ether solution (commercially available, top grade is pure), when the mice inertia, its extremity and head are fixed on to flat board above, alcohol disinfecting abdominal part, the execution of cutting open the belly rapidly.
To putting to death model mouses after 2 weeks and the contrast Mus carries out the liver contrast, its liver size shape as shown in Figure 5: fatty liver model is shown in a large amount of liver Fat Accumulations (Fig. 5 A).The matched group Hepar Mus has no change (Fig. 5 B).Use range estimation, liver size has obvious difference.
Embodiment 2
After two groups of mices are processed, 5ml from the blood sampling of the Mus heart respectively, timely separation of serum is in-20 ℃ of preservations; Take out mouse liver, it is 5 cm * 0. 3 cm of 1. 5 cm * 1. that hepatic tissue is divided into to size, be placed on respectively AAF mixed stationary liquid (ethanol, acetic acid, neutral formalin, V/V/V, referring to being permitted equality (Henan Medical Univ.'s journal, 1999,34 (4): the method for 75) introducing is fixed.
Adopt Leica-CM1900 type cryostats and Feather disposable blade to carry out respectively conventional frozen section to the hepatic tissue specimen two groups of rat livers, draw materials, common glue embedding (freezing), section, dyeing mounting afterwards.
Two groups of mice routines are carried out to pathologic finding (H& E dyeing); Rat liver carries out fat stains with oil red O method, dynamic analysis hepatic tissue athero.
Concrete steps are as follows: take model mice as example.
The model mouse murine liver tissue is conventional fixing with 10% formalin solution (V/V), frozen section, thick 10 μ m;
(take 0.5g oil red O, with 1,2-PD (Sigma, Cat#P4347), 100 ml dissolve preparation oil red O stain liquid, put in port grinding bottle and save backup;
Entering concentration after chip drying (in room temperature, 22 ± 2 ℃ of natural dryings) is that 50% ethanol (V/V) is slightly washed 5 seconds;
Oil red O dye liquor effect 8 minutes;
50% ethanol (V/V) differentiation, tap water stops differentiation;
Conventional haematoxylin is redyed core, and distilled water returns indigo plant, the glycerin gelatine mounting;
The Process and model mice of control mice is equal to, and at this, is not repeated.
Fat drop in hepatocyte takes on a red color, and it is blue that nucleus is, as shown in Figure 4.
Hepatic tissue and blood fatty acid analysis method, referring to (Clin Chim Acta, 1972 such as Cederblad; The method of 37:235-243) introducing.
Dynamic analysis hepatic tissue fat.Two groups of Hepar Mus after dyeing are carried out to dynamic analysis, the dynamic analysis hepatic tissue fat drawn is contrasted, draw hepatic tissue Fat Accumulation in fatty acid and total fatty acids dynamic change model process of establishing, hepatic tissue long-chain fatty acid, short-chain fatty acid and total fatty acids level (subordinate list); In peripheral blood, long-chain fatty acid, short-chain fatty acid and total fatty acids level change.As follows as the variation of fatty acid concentration in murine liver tissue:
the subordinate list Hepar Mus is fatty acid concentration variation (n=5, nMol/ gram weight in wet base hepatic tissue) in the time of dirty two weeks
| Group | Total fatty acids | Free fatty | Short-chain fatty acid | Long-chain fatty acid |
| Model mouse | 392.16±53.08* | 252.28±28.21* | 61.56±23.28* | 78.32±9.51* |
| The contrast Mus | 323.78±51.29 | 151.46±37.81 | 106.92±41.16 | 65.80±7.73 |
*P<0.05
Above proof is utilized this invention technology, can prepare desirable model, for the research of mankind NAFLD.
Embodiment 4
Under the low power optical microscope, the model mouse hepatic tissue occurs a large amount of
fat generation, as shown in the figure of the below of Fig. 4, make
hepatic tissue weight significantly increases; The contrast Mus without, as shown in the figure of Fig. 4 top.Clear in order further to see, under Powerful Light Microscope, observe, the model mouse hepatic tissue occurs that significant quantities of fat gathers obviously, the contrast Mus without.Figure as Fig. 4 right side.
Model mouse is through THP injection carnitine two weeks and matched group injecting normal saline (n=5/ group); Two groups of livers, the heart, lung and brain weights change, and as shown in Figure 6, find heavy (159.92 ± 22.79) mg of experimental group liver, matched group (104.86 ± 17.67) mg, group difference obviously (
p<0.05); And the heart, lung and cerebral tissue are heavy, slightly increase, but between group, be showed no notable difference (
p0.05), the THP antagonism causes the hepatic tissue fat generation, and Carnitine Content directly affects the liver lipid metabolism.
Claims (6)
1. a novel non-alcoholic fatty liver disease model preparation method is characterized in that: comprise the following steps:
Raise mice group with male 4～6 week age wild type (mice is raised in clean environment; Divide two groups at random, first group: model group: second group: control mice; Record body weight, active state every day, leave and take urine, leave and take hepatic tissue and make pathology inspection and lipid analysis, leave and take blood and make lipid analysis
Process experimental subject: with normal two groups of mices;
Set up model: to model mice, adopt abdominal cavity to transport the carrier that long-chain fatty acid enters the oxidation of line grain-------carnitine in antagonist;
Hepatic tissue and blood collection: respectively two groups of mices are placed in sealed container, add diethyl ether solution, when the mice inertia, its extremity and head are fixed on to flat board above, and the alcohol disinfecting abdominal part, cut open the belly rapidly, from the blood sampling of the Mus heart, take out hepatic tissue, be cut into size and be the 5 cm * 0. 3 cm piece of tissue of 1. 5 cm * 1., be placed on respectively in the AAF mixed stationary liquid fixing;
The rat liver specimen is carried out to conventional frozen section, draw materials, common glue bag frozen section, dyeing after mounting;
The model mice routine is carried out to pathologic finding------H& E dyeing rat liver carries out fat stains with oil red O method, dynamic analysis hepatic tissue athero;
The control mice routine is carried out to pathologic finding-------H& E dyeing rat liver carries out fat stains with oil red O method, dynamic analysis hepatic tissue fat;
By f) and dynamic analysis hepatic tissue fat g) drawn in step contrasted, draw fatty acid and total fatty acids dynamic change, hepatic tissue Fat Accumulation in the model process of establishing, in hepatic tissue long-chain fatty acid, short-chain fatty acid and total fatty acids, peripheral blood, long-chain fatty acid, short-chain fatty acid and total fatty acids level change.
2. a kind of novel non-alcoholic fatty liver disease model preparation method according to claim 1, it is characterized in that: described carnitine antagonist is 3-(2,2,2-trimethyl hydrazinium) propionate dihydrate, i.e. THP; According to the ABW of mice, be 0.05% calculating THP consumption by weight every day, with 0.85%NaCl, dissolves, and through one times/day of lumbar injection, injects 2～4 weeks.
3. a kind of novel non-alcoholic fatty liver disease model preparation method according to claim 1, it is characterized in that: mice is supported condition temporarily: described two groups of wild-type mices all are placed in humidity 55%, temperature is 22 ± 2 ℃, and the isoperibol that 12 hours daytime/Polygonm multiflorum Thunb replace is raised.
4. a kind of novel non-alcoholic fatty liver disease model preparation method according to claim 1, it is characterized in that: described control mice is with equivalent 0.85%NaCl solution, through lumbar injection.
5. a kind of novel non-alcoholic fatty liver disease model preparation method according to claim 1, it is characterized in that: the method for described oil red O configuration dye liquor is as follows: take 0.5g oil red O, with 1,2-PD (Sigma, Cat#P4347) 100 ml dissolve, and put in port grinding bottle and save backup.
6. a kind of novel non-alcoholic fatty liver disease model preparation method according to claim 1, it is characterized in that: described f) in step, rat liver carries out fat stains with oil red O method: method is as follows: enter 50% ethanol after the b2 chip drying and slightly wash; C3, room temperature (22 ± 2 ℃) soak and put oil red O dye liquor 8 minutes; 50% ethanol differentiation, tap water stops differentiation; Conventional haematoxylin is redyed core, and distilled water returns indigo plant, the glycerin gelatine mounting; Fat drop in hepatocyte takes on a red color, and it is blue that nucleus is.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105052830A (en) * | 2015-08-04 | 2015-11-18 | 施军平 | Fatty-liver-related liver cancer model building method based on knockout mice |
| CN105400732A (en) * | 2015-11-19 | 2016-03-16 | 南京理工大学 | Establishment method for alcoholic fatty liver zebra fish model |
| CN105850867A (en) * | 2016-03-28 | 2016-08-17 | 大连大学 | Method for modeling mouse models with non-alcoholic fatty liver disease (NAFLD) |
| CN106614263A (en) * | 2016-09-19 | 2017-05-10 | 南通大学附属医院 | Application of CPT-II in malignant transformation process induced by fat accumulation of liver cells |
| CN107197823A (en) * | 2017-06-20 | 2017-09-26 | 遵义医学院 | A kind of Establishment of Rat Model method of NASH |
| CN109105333A (en) * | 2017-06-22 | 2019-01-01 | 中美冠科生物技术（太仓）有限公司 | Animal model for nonalcoholic fatty liver disease |
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Cited By (8)
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| CN105052830A (en) * | 2015-08-04 | 2015-11-18 | 施军平 | Fatty-liver-related liver cancer model building method based on knockout mice |
| CN105052830B (en) * | 2015-08-04 | 2019-06-04 | 施军平 | A kind of fatty liver associated hepatocellular carcinoma model building method based on knock out mice |
| CN105400732A (en) * | 2015-11-19 | 2016-03-16 | 南京理工大学 | Establishment method for alcoholic fatty liver zebra fish model |
| CN105850867A (en) * | 2016-03-28 | 2016-08-17 | 大连大学 | Method for modeling mouse models with non-alcoholic fatty liver disease (NAFLD) |
| CN106614263A (en) * | 2016-09-19 | 2017-05-10 | 南通大学附属医院 | Application of CPT-II in malignant transformation process induced by fat accumulation of liver cells |
| CN107197823A (en) * | 2017-06-20 | 2017-09-26 | 遵义医学院 | A kind of Establishment of Rat Model method of NASH |
| CN109105333A (en) * | 2017-06-22 | 2019-01-01 | 中美冠科生物技术（太仓）有限公司 | Animal model for nonalcoholic fatty liver disease |
| CN109105333B (en) * | 2017-06-22 | 2022-08-05 | 浙江药源新地生物科技有限公司 | Animal model for non-alcoholic fatty liver disease |
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